NGF – Hereditary Sensory and Autonomic Neuropathy Type V

Hereditary Sensory and Autonomic Neuropathy type V (HSAN V) is an autosomal recessive disorder marked by congenital insensitivity to deep pain and temperature with normal cognitive function. The disease arises from bi-allelic loss-of-function variants in the nerve growth factor gene (NGF), which encodes the neurotrophin critical for survival and differentiation of peripheral nociceptors and sympathetic neurons. HSAN V patients exhibit severe reduction of unmyelinated (C-fiber) and thin myelinated (Aδ) fibers, resulting in impairment of nociceptive pathways without central nervous system deficits ([PMID:14976160]).

Genetic mapping in a large Swedish consanguineous family with four affected individuals established linkage to chromosome 1p11.2-p13.2 and revealed a homozygous R100W (c.661C>T) loss-of-function NGF variant segregating with HSAN V ([PMID:14976160]). Subsequent reports identified additional unrelated probands carrying homozygous null or missense NGF alleles: a c.361C>T (p.Arg121Trp) mutation disrupting furin cleavage ([PMID:30296891]) and a c.241C>T (p.Arg81Ter) nonsense allele ([PMID:21387003]). Segregation analysis confirmed recessive inheritance in all families, with complete cosegregation of bi-allelic NGF variants in affected siblings and heterozygous carriers remaining asymptomatic.

Across these studies, six homozygous probands have been reported with three distinct variant classes: two nonsense (c.241C>T (p.Arg81Ter), c.661C>T (p.Arg221Trp)), one missense at the pro-peptide cleavage site (c.361C>T (p.Arg121Trp)) ([PMID:14976160], [PMID:30296891], [PMID:21387003]). No recurrent or founder alleles beyond the Swedish R100W variant have been described. Carrier frequency is undetermined due to disease rarity. Unaffected heterozygotes show normal pain perception but may display mild small-fiber neuropathy on biopsy, underscoring the recessive mechanism ([PMID:18420729]).

Functional assays demonstrate that the p.Arg121Trp mutation abolishes conversion of proNGF to mature NGF-β and markedly reduces TrkA autophosphorylation and downstream MAPK activation in PC12 cells ([PMID:30296891]). The R100W variant selectively impairs p75^NTR binding without compromising TrkA affinity, leading to intact trophic support but absent nociceptive signaling in vitro ([PMID:19945432]). PC12 bioassays confirm preserved neurotrophic activity yet loss of nociceptor sensitization, consistent with patient phenotypes and reinforcing a haploinsufficiency/LOF mechanism.

In vivo rodent models of the NGF^R100W mutation recapitulate the clinical HSAN V phenotype: heterozygous knock-in mice exhibit normal cognitive performance but have attenuated mechanical allodynia and reduced intraepidermal nerve fiber density, while central cholinergic neurons remain intact ([PMID:31685654]). Intradermal injection of NGF^R100W in adult rats fails to induce acute hyperalgesia but retains chronic TrkA-dependent effects, delineating the specific role of p75^NTR signaling in pain transmission ([PMID:29483280]).

Together, genetic and experimental data provide strong evidence for a definitive NGF–HSAN V association. Bi-allelic NGF LOF variants consistently lead to isolated congenital pain insensitivity with preserved cognition, underscoring the clinical utility of NGF genetic testing for diagnosis, genetic counseling, and targeted development of ‘‘painless’’ NGF analogs. Key Take-home: Recessive NGF loss-of-function mutations unequivocally cause HSAN V, enabling precise molecular diagnosis and informing pain-modulating therapeutic strategies.

References

• Human molecular genetics • 2004 • A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. PMID:14976160
• Molecular pain • 2018 • A third HSAN5 mutation disrupts the nerve growth factor furin cleavage site. PMID:30296891
• PloS one • 2011 • Taking pain out of NGF: a "painless" NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity. PMID:21387003
• The Journal of neuroscience • 2019 • The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V. PMID:31685654
• Biochemical and biophysical research communications • 2010 • In vitro receptor binding properties of a "painless" NGF mutein, linked to hereditary sensory autonomic neuropathy type V. PMID:19945432

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